This invention relates to bicyclic pyrrolyl amides and pharmaceutical compositions comprising bicyclic pyrrolyl amides. This invention also relates to the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia, using the bicyclic pyrrolyl amides.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less then satisfactory.
The use of insulin requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use, or an agent may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy. Hypoglycemic agents that have fewer side effects or succeed where others fail are needed.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of xe2x80x9cfatty streaksxe2x80x9d in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, give rise to development of the xe2x80x9cfibrous plaque,xe2x80x9d which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extra cellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified tog and necrotic, advancing to the xe2x80x9ccomplicated lesion,xe2x80x9d which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of xe2x80x9cnormalxe2x80x9d are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Hypertension (or high blood pressure) is a condition which occurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While such xe2x80x9cessentialxe2x80x9d hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been elucidated. Additionally, many patients display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder.
It is known that hypertension can directly lead to heart failure, renal failure and stroke (brain hemorrhaging). These conditions are capable of causing death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a patient and can lead to death.
The exact cause of essential hypertension is unknown, though a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin, aldosterone system), excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in constricted blood vessels and genetic factors.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus, a broad range of beta-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure and brain hemorrhaging. However, the development of atherosclerosis or heart disease due to hypertension over a long period of time remains a problem. This implies that although high blood pressure is being reduced, the underlying cause of essential hypertension is not responding to this treatment.
Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts to promote vascular cell growth and increase renal sodium retention, among other things. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviate hypertension.
Cardiac hypertrophy Is a significant risk factor in the development of sudden death, myocardial infarction, and congestive heart failure. These cardiac events are due, at least in part, to increased susceptibility to myocardial injury after ischemia and reperfusion that can occur in out-patient as well as perioperative settings. There is an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks for myocardial infarction or death. Some 7 million patients undergoing non-cardiac surgery are considered to be at risk, with incidences of perioperative death and serious cardiac complications as high as 20-25% in some series. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently no marketed drug therapy in this area which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients. The mechanism(s) responsible for the myocardial injury observed after Ischemia and reperfusion is not fully understood. It has been reported (M. F. Allard, et al., Am. J. Physiol., 267: H66-H74 (1994)) that xe2x80x9cpre ischemic glycogen reduction . . . is associated with improved post ischemic left ventricular functional recovery in hypertrophied rat heartsxe2x80x9d.
In addition to myocardial ischemia, other tissues can undergo ischemia and be damaged resulting in serious problems for the patient. Examples of such tissues include cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, or intestinal tissue.
Hepatic glucose production is an important target for NIDDM therapy. The liver is the major regulator of plasma glucose levels in the post absorptive (fasted) state, and the rate of hepatic glucose production in NIDDM patients is significantly elevated relative to normal individuals. Likewise, in the postprandial (fed) state, where the liver has a proportionately smaller role in the total plasma glucose supply, hepatic glucose production is abnormally high in NIDDM patients.
Glycogenolysis is an important target for interruption of hepatic glucose production. The liver produces glucose by glycogenolysis (breakdown of the glucose polymer glycogen) and gluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors). Several lines of evidence indicate that glycogenolysis may make an important contribution to hepatic glucose output in NIDDM. First, in normal post absorptive man, up to 75% of hepatic glucose production is estimated to result from glycogenolysis. Second, patients having liver glycogen storage diseases, including Hers"" disease (glycogen phosphorylase deficiency), display episodic hypoglycemia. These observations suggest that glycogenolysis may be a significant process for hepatic glucose production.
Glycogenolysis is catalyzed in liver, muscle, and brain by tissue-specific isoforms of the enzyme glycogen phosphorylase. This enzyme cleaves the glycogen macromolecule to release glucose-1-phosphate and a new shortened glycogen macromolecule. Several types of glycogen phosphorylase inhibitors have been reported to date: glucose and glucose analogs [Martin, J. L. et al., Biochemistry, 30.10101 (1991)]; caffeine and other purine analogs [Kasvinsky, P. J. et al., J. Biol. Chem., 253: 3343-3351 and 9102-9106 (1978)]; substituted N-(indole-2-carbonyl-amides [PCT Publication Number WO 96/39385]; and substituted N-(indole-2-carbonylglycinamides [PCT Publication Number WO 96/39384]. These compounds and glycogen phosphorylase inhibitors in general, have been postulated to be of use for the treatment of NIDDM by decreasing hepatic glucose production and lowering glycemia. [Blundell, T. B. et al, Diabetologia, 35: Suppl. 2, 569-576 (1992) and Martin et al., Biochemistry, 30: 10101 (1991)].
Myocardial ischemic injury can occur in outpatient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Although there are a variety of hyperglycemia, hypercholesterolemia, hypertension, hyperlipidemia, atherosclerosis and tissue ischemia therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.
The present invention provides compounds of Formula I: 
stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs,
wherein
Q is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
each Z and X are independently (C, CH or CH2), N, O or S;
X1 is NRa, xe2x80x94CH2xe2x80x94, O or S;
each - - - is independently a bond or is absent, provided that both - - - are not simultaneously bonds;
R1 is hydrogen, halogen, xe2x80x94OC1-C8alkyl, xe2x80x94SC1-C8alkyl, xe2x80x94C1-C8alkyl, xe2x80x94CF3, xe2x80x94NH2, xe2x80x94NHC1-C8alkyl, xe2x80x94N(C1-C8alkyl)2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2C1-C8alkyl, xe2x80x94C2-C8alkenyl, or xe2x80x94C2-C8alkynyl;
each Ra and Rb is independently hydrogen or xe2x80x94C1-C8alkyl;
Y is 
xe2x80x83or absent;
R2 and R3 are independently hydrogen, halogen, xe2x80x94C1-C8alkyl, xe2x80x94CN, xe2x80x94Cxe2x89xa1Cxe2x80x94Si(CH3)3, xe2x80x94OC1-C8alkyl, xe2x80x94SC1-C8alkyl, xe2x80x94CF3, xe2x80x94NH2, xe2x80x94NHC1-C8alkyl, xe2x80x94N(C1-C8alkyl)2, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CO2C1-C8alkyl, xe2x80x94C2-C8alkenyl, or xe2x80x94C2-C8alkynyl, or R2 and R3 together with the atoms on the ring to which they are attached form a five or six membered ring containing from 0 to 3 heteroatoms and from 0 to 2 double bonds;
R4 is xe2x80x94C(xe2x95x90O)xe2x80x94A;
A is xe2x80x94NRdRd, xe2x80x94NRaCH2CH2ORa, 
each Rd is independently hydrogen, C1-C8alkyl, C1-C8alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
each Rc is independently hydrogen, xe2x80x94C(xe2x95x90O)ORa, xe2x80x94ORa, xe2x80x94SRa, or xe2x80x94NRaRa; and
each n is independently 1-3.
In a preferred embodiment of the compounds of Formula I, Rb and R1 are hydrogen.
In another preferred embodiment of the compounds of Formula I,
Rb is hydrogen;
R1 is hydrogen;
Y is 
and A is 
In another preferred embodiment of the compounds of Formula I,
Rb is hydrogen;
R1 is hydrogen;
Y is absent; and
A is 
In another preferred embodiment of the compounds of Formula I,
Rb is hydrogen;
R1 is hydrogen;
Z is C;
X is O or S;
Y is absent;
A is 
R2 is hydrogen; and
R3 is hydrogen, halogen or methyl.
In another preferred embodiment of the compounds of Formula I,
Q is phenyl and A is 
In another preferred embodiment, the invention provides compounds of Formula I 
stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs,
wherein
Q is phenyl;
(Z is S and X is C), (Z is C and X is S), or (Z is C and X is O);
each - - - is independently a bond or is absent, provided that both - - - are not simultaneously bonds;
R1 is hydrogen or halogen,
each Ra and Rb is independently hydrogen or C1-C8alkyl;
Y is 
xe2x80x83or absent;
R2 and R3 are independently hydrogen, halogen, C1-C8alkyl, xe2x80x94CN, xe2x80x94Cxe2x89xa1CSi(CH3)3, or C2-C8alkynyl, or R2 and R3 together with the atoms on the ring to which they are attached form a five or six membered ring containing from 0 to 3 heteroatoms and from 0 to 2 double bonds;
R4 is xe2x80x94C(xe2x95x90O)xe2x80x94A;
A is xe2x80x94NRdRd, 
each Rd is independently C1-C8alkyl;
each Rc is independently hydrogen, xe2x80x94OH, or xe2x80x94C(xe2x95x90O))C1-C8alkyl;
each n is independently 1-3.
In another preferred embodiment of the compounds of Formula I, 
Also provided are pharmaceutical compositions comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing atherosclerosis, the methods comprising the step of administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetes, the methods comprising the step of administering to a patient having diabetes a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrug.
In a preferred embodiment of the methods of treating diabetes, the diabetes is non-insulin dependent diabetes mellitus (Type II).
In another preferred embodiment of the methods of treating diabetes, the diabetes is insulin dependent diabetes mellitus (Type I).
Also provided are methods of treating insulin resistance, the methods comprising the step of administering to a patient having insulin resistance a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetic neuropathy, the methods comprising the step of administering to a patient having diabetic neuropathy a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetic nephropathy, the methods comprising the step of administering to a patient having diabetic nephropathy a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetic retinopathy, the methods comprising the step of administering to a patient having diabetic retinopathy a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating cataracts, the methods comprising the step of administering to a patient having cataracts a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hypercholesterolemia, the methods comprising the step of administering to a patient having hypercholesterolemia or at risk of having hypercholesterolemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hypertriglyceridemia, the methods comprising the step of administering to a patient having hypertriglyceridemia or at risk of having hypertriglyceridemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hyperlipidemia, the methods comprising the step of administering to a patient having hyperlipidemia or at risk of having hyperlipidemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating hyperglycemia, the methods comprising the step of administering to a patient having hyperglycemia or at risk of having hyperglycemia therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating hypertension, the methods comprising the step of administering to a patient having hypertension or at risk of having hypertension a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing tissue ischemia, the methods comprising the step of administering to a patient having tissue ischemia or at risk of having tissue ischemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing myocardial ischemia, the methods comprising the step of administering to a patient having myocardial ischemia or at risk of having myocardial ischemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of inhibiting glycogen phosphorylase, the methods comprising the step of administering to a patient in need of glycogen phosphorylase inhibition, a glycogen phosphorylase inhibiting amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
The present invention provides the compounds:
6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
2-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
(xc2x1)-2-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [1-benzyl-2((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-bromo-6H-thieno[2,3-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2,4-dichloro-6H-thieno[2,3-b]pyrrole-5carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
(xc2x1)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [1-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
(xc2x1)-2-bromo-4H-furo[3,2-b]pyrrole-carboxylic acid [1-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-bromo-4H-furo[3,2-b]pyrrole-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
6H thieno[2,3-b]pyrrole-5carboxylic add [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-bromo-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2,4-dichloro-6H-thieno[2,3-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2oxo-ethyl]-amide;
2-cyano-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-morpholin-4-yl-2-oxo-ethyl]-amide;
2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-dimethylcarbamoyl-2-phenyl-ethyl]-amide;
2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(1,1-dioxo-1-thiazolidin-3-yl)-2-oxo-ethyl]-amide;
1-{(2S)-[(2-chloro-6H-thieno[2,3-b]pyrrole-5-carbonyl)-amino]-3-phenyl-propionyl}-piperidine-4-carboxylic acid ethyl ester;
2-bromo-6H-thieno[2,3-b]pyrrole5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2oxo-ethyl]-amide;
2-methyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-trimethylsilanylethynyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
2-ethynyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
2-fluoro-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2oxo-ethyl]-amide;
2-cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2,3-hydroxy-azetidin-1-yl)-2oxo-ethyl]-amide;
2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3oxo-propyl]-amide;
1-{(2S)-[(2-chloro-6H-thieno[2,3-b]pyrrole-5-carbonyl)amino]-3-phenyl-propionyl}-piperidine-4-carboxylic add;
3-chloro-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
3-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
3-bromo-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2hydroxy-3-oxo-propyl]-amide;
2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
2-chloro-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-8dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
3-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
3-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
2-cyano-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
3-bromo-4H-furo[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
3-bromo-4H-furo[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
4H-1,7-dithia-4-aza-cyclopenta[a]pentalene-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
4H-1,7-dithia-4-aza-cyclopenta[a]pentalene-5-carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-chloro-3-methyl-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-chloro-3-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide;
2-methylsulfanyl-6H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide;
2-Bromo-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-(1,1-dioxo-1-thiazolidin-3-yl)-2-oxo-ethyl]-amide;
2-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-morpholin-4-yl-2-oxo-ethyl]-amide;
2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;
2-bromo-4H-thieno[3,2-b]pyrrole-5carboxylic acid [(1S)-benzyl-2-((3R,4R)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide; and
2-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide, and stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds, and pharmaceutically acceptable salts of the prodrugs.
Also provided are kits for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or cataracts in a patient having diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or cataracts, the kits comprising:
a) a first pharmaceutical composition comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of Formula I, and pharmaceutically acceptable salts of the prodrugs;
b) a second pharmaceutical composition comprising a second compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or cataracts; and
c) a container for containing the first and second compositions.
In a preferred embodiment of the kits, the second compound is selected from:
insulin and insulin analogs;
GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH2;
sulfonylureas and analogs;
biguanides;
xcex12-antagonists;
imidazolines;
glitazones (thiazolidenediones);
PPAR-gamma agonists;
fatty acid oxidation inhibitors;
xcex1-glucosidase inhibitors;
xcex2-agonists;
phosphodiesterase inhibitors;
lipid-lowering agents:
antiobesity agents
vanadate, vanadium complexes and peroxovanadium complexes;
amylin antagonists;
glucagon antagonists;
gluconeogenesis inhibitors;
somatostatin analogs and antagonists; and
antilipolytic agents.
In another preferred embodiment of the kits, the second compound is selected from LysPro insulin, GLP-1 (7-37) (insulinotropin), GLP-1 (7-36)-NH2, chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide, glimepiride, repaglinide, meglitinide; metformin, phenformin, buformin, midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone, clomoxir, etomoxir. acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, L-386,398; benfluorex, fenfluramine, Naglivan(copyright), (bis(cysteinamide N-octyl)oxovanadium) acpimox, WAG 994, Symlin(trademark), (pramlintide acetate)-AC2993 and nateglinide.
In still another preferred embodiment of the kits, the second compound is selected from insulin, sulfonylureas, biguanides, and thiazolidinediones.
Also provided are kits for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia in a patient having diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia, the kits comprising:
a) a first pharmaceutical composition comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of Formula I, and pharmaceutically acceptable salts of the prodrugs;
b) a second pharmaceutical composition comprising a second compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia; and
c) a container for containing the first and second compositions.
Also provided are methods of treating diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia, the method comprising the step of administering to a patient having diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia, a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs in combination with at least one additional compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.
Also provided are pharmaceutical compositions comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs and at least one additional compound useful to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.
The present invention relates to compounds of Formula I, stereoisomers of compounds of Formula I, pharmaceutically acceptable salts of compounds of Formula I, prodrugs of compounds of Formula I, and pharmaceutically acceptable salts of the prodrugs of compounds of Formula I. The invention also relates to methods of treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia, and to pharmaceutically acceptable compositions comprising a compound of Formula I, stereoisomers of compounds of Formula I, pharmaceutically acceptable salts of compounds of Formula I, prodrugs of compounds of Formula I, and pharmaceutically acceptable salts of the prodrugs of compounds of Formula I.
Certain terms that are used in this application are defined below.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, sec-butyl, pentyl, and hexyl. Preferred alkyl groups are C1-C8alkyl.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy groups are C1-C8alkoxy.
The term xe2x80x9chalogenxe2x80x9d means chlorine, fluorine, bromine or iodine.
The term xe2x80x9calkenylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds.
The term xe2x80x9calkynylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic, hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred cycloalkyl groups are C3-C8cyloalkyl. It is also possible for the cycloalkyl group to have one or more double bonds, but is not aromatic. Examples of cycloalkyl groups having double bonds include cyclopentenyl, cyclohexenyl. cyclohexadienyl, cyclobutadienyl, and the like.
The term xe2x80x9cperfluoroalkylxe2x80x9d means an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms.
The term xe2x80x9cacylxe2x80x9d means a group derived from an organic acid (xe2x80x94COOH) by removal of the hydroxy group (xe2x80x94OH).
The term xe2x80x9carylxe2x80x9d means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl.
The term xe2x80x9cheteroatomxe2x80x9d includes oxygen, nitrogen, sulfur, and phosphorous.
The term xe2x80x9cheteroarylxe2x80x9d means a cyclic, aromatic hydrocarbon in which one or more carbon atoms have been replaced with a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyddyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo[b]thienyl. Preferred heteroaryl groups are five or six membered rings and contain from one to three heteroatoms.
The term xe2x80x9cheterocycloalkylxe2x80x9d means a cycloalkyl group in which one or more of the carbon atoms has been replaced with a heteroatom. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperadyl, and pyrrolidinyl. Preferred heterocycloalkyl groups are five or six membered rings and contain from one to three heteroatoms. It is also possible for the heterocycloalkyl group to have one or more double bonds, but is not aromatic. Examples of heterocycloalkyl groups containing double bonds include dihydrofuran, and the like.
It is also noted that the cyclic ring groups, i.e., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, can comprise more than one ring. For example, the naphthyl group is a fused bicyclic ring system. It is also intended that the present invention include ring groups that have bridging atoms, or ring groups that have a spiro orientation.
Representative examples of five to six membered aromatic rings, optionally having one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, and pyrazinyl.
Representative examples of partially saturated, fully saturated or fully unsaturated five to eight membered rings, optionally having one to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl, and 1,3-oxathiolyl.
Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyndazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-(3 oxathiazinyl, and 1,4,2-oxadiazinyl.
Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl.
Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)pyridinyl, pyrido(3,2-b)pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
A cyclic ring group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term xe2x80x9cpyridylxe2x80x9d includes 2-, 3-, or 4-pyridyl, and the term xe2x80x9cthienylxe2x80x9d includes 2-, or 3-thienyl.
The term xe2x80x9csubstitutedxe2x80x9d means that a hydrogen atom on an organic molecule has been replaced with a different atom or with a molecule. The atom or molecule replacing the hydrogen atom is called a substituent. Examples of suitable substituents include, halogens, xe2x80x94OC1-C8alkyl, xe2x80x94C1-C8alkyl, xe2x80x94CH3, xe2x80x94NH2, xe2x80x94NHC1-C8alkyl, xe2x80x94N(C1-C8alkyl)2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2C1-C8alkyl, and the like.
The symbol xe2x80x9cxe2x88x92xe2x80x9d represents a covalent bond.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of a compound that ameliorates, attenuates, or eliminates one or more symptom of a particular disease or condition or prevents or delays the onset of one of more symptom of a particular disease or condition.
The term xe2x80x9cpatientxe2x80x9d means animals, such as dogs, cats, cows, horses, sheep, and humans. Particularly preferred patients are mammals. The term patient includes males and females.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the patient.
The phrases xe2x80x9ca compound of the present invention, compounds of the present invention, a compound of Formula I, or a compound in accordance with Formula Ixe2x80x9d and the like, includes the stereoisomers of the compound(s), pharmaceutically acceptable salts of the compound(s), prodrugs of the compound(s), and pharmaceutically acceptable salts of the prodrugs.
The terms xe2x80x9creaction-inert solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d refer to a solvent or mixture of solvents that does not interact with starting materials, reagents, intermediates or products in a manner that adversely affects the desired product
The terms xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d include preventative (e.g., prophylactic) and palliative treatment.
The term xe2x80x9cglycogen phosphorylase inhibitorxe2x80x9d refers to any substance or agent or any combination of substances and/or agents that reduces, retards, or eliminates the enzymatic action of glycogen phosphorylase. The currently known enzymatic action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a glycogen macromolecule and inorganic phosphate to glucose-1-phosphate and a glycogen macromolecule which is one glucosyl residue shorter than the original glycogen macromolecule (forward direction of glycogenotysis).
A patient in need of glycogen phosphorylase inhibition is a patient having a disease or condition in which glycogen phosphorylase plays a role in the disease of condition. Examples of patients in need of glycogen phoshphorylase inhibition include patients having diabetes (including Type I and Type II, impaired glucose tolerance, insulin resistance, and the diabetic complications, such a nephropathy, retinopathy, neuropathy and cataracts), hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and tissue ischemia.
The characteristics of patients at risk of having atherosclerosis are well known to those skilled in the art and include, patients who have a family history of cardiovascular disease, including hypertension and atherosclerosis, obese patients, patient who exercise infrequently, patients with hypercholesterolemia, patients having high levels of low density lipoprotein (LDL), patients having low levels of high density lipoprotein (HDL), and the like.
Patients at risk of having myocardial ischemia and other tissue ischemias are also well known to those skilled in the art and include patients undergoing or having undergone surgery, trauma or great stress.
The compounds of the present invention are administered to a patient in a c, therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
In addition, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds. The other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously, or sequentially. For example, in the case of tablets, the active compounds may be found in one tablet or in separate tablets, which can be administered at once or sequentially in any order. In addition, it should be recognized that the compositions may be different forms. For example, one or more compound may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.
Since one aspect of the present invention contemplates the treatment of the disease/conditions with a combination of pharmaceutically active agents that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, bags, and the like. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . xe2x80x9d etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a compound of the present invention can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this and aid in correct administration of the active agents.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The compounds of the present invention and other pharmaceutically active agents, if desired, can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quatemary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants. The active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required. Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient. The specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is well within the ordinary skill in the art.
The following paragraphs describe exemplary formulations, dosages etc. useful for non-human animals. The administration of a compound of the present invention can be effected orally or non-orally, for example by injection. An amount of a compound of the present invention is administered such that an effective dose is received, generally a daily dose which, when administered orally to an animal is usually between 0.01 and 100 mg/kg of body weight, preferably between 0.1 and 50 mgtkg of body weight. Conveniently, the medication can be carried in the drinking water so that a therapeutic dosage of the agent is ingested with the daily water supply. The agent can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water soluble salt). Conveniently, the active ingredient can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate. A premix or concentrate of therapeutic agent in a carrier is more commonly employed for the inclusion of the agent in the feed. Suitable carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, gurea, bone meal, and mineral mixes such as are commonly employed in poultry feeds. A particularly effective carrier Is the respective animal feed itself; that is, a small portion of such feed. The carrier facilitates uniform distribution of the active materials in the finished feed with which the premix is blended. It is important that the compound be thoroughly blended into the premix and, subsequently, the feed. In this respect, the agent may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or In a volatile organic solvent and then blended with the carrier. It will be appreciated that the proportions of active material in the concentrate are capable of wide variation since the amount of agent in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of therapeutic agent.
High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound according to the invention. The mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.
If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing a compound of the invention with a sufficient amount of animal feed to provide from about 10xe2x88x923 to about 500 ppm of the compound in the feed or water.
The preferred medicated swine, cattle, sheep and goat feed generally contain from about 1 to about 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to about 300 grams per ton of feed.
The preferred poultry and domestic pet feeds usually contain about 1 to about 400 grams and preferably about 10 to about 400 grams of active ingredient per ton of feed.
For parenteral administration in animals, the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal.
In general, parenteral administration involves injection of a sufficient amount of a compound of the present invention to provide the animal with about 0.01 to about 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from about 0.1 to about 50 mg/kg/day.
Paste formulations can be prepared by dispersing the active compound in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
Pellets containing an effective amount of a compound of the present invention can be prepared by admixing a compound of the present invention with a diluent such as carbowax, camuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper active agent in the level animal""s body.
The term pharmaceutically acceptable salts, esters, amides, or prodrugs means the carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use with patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
The term xe2x80x9csaltsxe2x80x9d refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quatemary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J Pharm Sci, 66: 1-19 (1977).
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of the present invention, if applicable, include C1-C8alkyl esters. Acceptable esters also include C5-C7cycloalkyl esters, as well as arylalkyl esters such as benzyl. C1-C4 alkyl esters are preferred. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.
Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include amides derived from ammonia, primary C1-C8alkyl amines, and secondary C1-C8dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 primary alkyl amines, and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.
The term xe2x80x9cprodrugxe2x80x9d means compounds that are transformed in vivo to yield a compound of Formula I. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if the compound of the invention contains a carboxylic add functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the add group with a group such as (C1-C8alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as xcex2dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.
Similarly, if the compound of the present invention comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, xcex1-amino(C1-C4)alkanoyl, arylacyl and xcex1-aminoacyl, or xcex1-aminoacyl-xcex1-aminoacyl, where each xcex1-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, xe2x80x94P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
If the compound of the present invention comprises an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRRxe2x80x2-carbonyl where R and R1 are each independently ((C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural xcex1-aminoacyl or natural xcex1-aminoacyl-natural xcex1-aminoacyl, xe2x80x94C(OH)C(O)OY wherein (Y is H, (C1-C6)alkyl or benzyl), xe2x80x94C(OY0)Y1 wherein Y0 is (C1-C4) alkyl and Y1 is ((C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N- or di-N,N-(C1-C6)alkylaminoalkyl, xe2x80x94C(Y2)Y3 wherein Y2 is H or methyl and Y3 is mono-N- or di-N,N-(C1-C6)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.
The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, If the compound contains a double bond, both the cis and trans forms, as well as mixtures, are contemplated.
Diasteromeric mixtures can be separated into their individual stereochemical components on the basis of their physical chemical differences by methods known per se, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of this invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms.
It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the imidazole moiety are included in this invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention.
Those skilled in the art will recognize that the compound names contained herein may be based on a particular tautomer of a compound. While the name for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the name of the particular tautomer and included as part of the invention.
It is also intended that the invention disclosed herein encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
The present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 16O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
In general the compounds of this invention can be made by processes which include processes analogous to those known in the chemical arts, particularly in light of the description contained herein.
In another aspect, the present invention concerns the treatment of diabetes, including impaired glucose tolerance, insulin resistance, insulin dependent diabetes mellitus (Type I) and non-insulin dependent diabetes mellitus (NIDDM or Type II). Also included in the treatment of diabetes are the treatment of the diabetic complications, such as neuropathy, nephropathy, retinopathy or cataracts.
Diabetes can be treated by administering to a patient having diabetes (Type I or Type II), insulin resistance, impaired glucose tolerance, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of the present invention. It is also contemplated that diabetes be treated by administering a compound of the present invention or an other glycogen phosphorylase inhibitor in combination with an additional agent that can be used to treat diabetes and/or obesity. Preferred gylcogen phosphorylase inhibitors that are useful in combination with other agents useful to treat diabetes and/or obesity include those of Formula I. Additional preferred gylcogen phosphorylase inhibitors are disclosed in PCT publications WO 96/39384 and WO 96/39385.
Representative agents that can be used to treat diabetes include insulin and insulin analogs: (e.g., LysPro insulin. inhaled formulations comprising insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)NH2; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; xcex12-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, insulinotropin, exendin-4, BTS-67582, A-4166; glitazones: ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone; PPAR-gamma agonists; RXR agonists: JTT-501, MCC-555, MX-6054, DRF2593, GI-262570, KRP-297, LG100268; fatty acid oxidaton inhibitors: clomoxir, etomoxir; xcex1-glurosidase inhibitors: precose, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; xcex2-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type: sildenafil, L686398: L-386,398; lipid-lowering agents: benfluorex, atorvastatin; antiobesity agents: fenfluramine, orlistat, sibutramine; vanadate and vanadium complexes (e.g., Naglivan(copyright)) and peroxovanadium complexes; amylin antagonists: pramlintide, AC-137; lipoxygenase inhibitors: masoprocal; somatostatin analogs: BM-23014, seglitide, octreotide; glucagon antagonists: BAY 276-9955; insulin signaling agonists, insulin mimetics, PTP1B inhibitors: L-783281, TER17411, TER17529; gluconeogenesis inhibitors:GP3034; somatostatin analogs and antagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994; glucose transport stimulating agents: BM-130795; glucose synthase kinase inhibitors: lithium chloride, CT98014, CT98023; galanin receptor agonisnts; MTP inhibitors such as those disclosed in U.S. provisional patent application No. 60/164,803; growth hormone secretagogues such as those disclosed in PCT publication numbers WO 97/24369 and WO 98/58947; NPY antagonists: PD-160170, BW-383, BW1229, CGP-71683A, NGD 95-1, L-152804; Anorectic agents including 5-HT and 5-HT2C receptor antagonists and/or mimetics: dexfenfluramine, Prozac(copyright), Zoloft(copyright); CCK receptor agonists: SR-27897B; galanin receptor antagonists; MCR-4 antagonists: HP-228; leptin or mimetics:leptin; 11-beta-hydroxysteroid dehydrogenase type-I inhibitors; urocortin mimetics, CRF antagonists, and CRF binding proteins: RU486, urocortin. Other anti-diabetic agents that can be used in combination with a glycogen phosphorylase inhibitor include ergoset and D-chiroinositol. Any combination of agents can be administered as described above.
In addition to the categories and compounds mentioned above, gylcogen phosphorylase inhibitors, preferrably the compounds of the present invention, can be administered in combination with thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors, or sorbitol dehydrogenase inhibitors, or combinations thereof, to treat or prevent diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia, particularly myocardial ischemia.
It is generally accepted that thyroid hormones, specifically, biologically active iodothyronines, are critical to normal development and to maintaining metabolic homeostasis. Thyroid hormones stimulate the metabolism of cholesterol to bile adds and enhance the lipolytic responses of fat cells to other hormones. U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and 5,061,798 disclose certain thyroid hormone mimetics (thyromimetics), namely, 3,5-dibromo-3xe2x80x2-[6-oxo-3(1H)pyridazinylmethyl]-thyronines. U.S. Pat. No. 5,284,971 discloses certain thyromimetic cholesterol lowering agents, namely, 4-(3-cyclohexyl4hydroxy or -methoxy phenylsulfonyl)-3,5 dibromo-phenylacetic compounds. U.S. Pat. Nos. 5,401,772; 5,654,468; and 5,569,674 disclose certain thyromimetics that are lipid lowering agents, namely, heteroacetic acid derivatives. In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. For example, N. Yokoyama, et al. in an article published in the Journal of Medicinal Chemistry, 38 (4): 695-707 (1995) describe replacing a xe2x80x94CH2 group in a naturally occurring metabolite of T3 with an xe2x80x94NH group resulting in xe2x80x94HNCOCO2H. Likewise, R. E. Steele et al. in an article published in International Congressional Service (Atherosclerosis X) 1066: 321-324 (1995) and Z. F. Stephan et al. in an article published in Atherosclerosis, 126: 53-63 (1996), describe certain oxamic acid derivatives useful as lipid-lowering thyromimetic agents, yet devoid of undesirable cardiac activities. Other useful thyromimetics that can be used in combination with a glycogen phosphorylase inhibitor include CGS-26214.
Each of the thyromimetic compounds referenced above and other thyromimetic compounds can be used in combination with the compounds of the present invention to treat or prevent diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or issue ischemia.
The compounds of the present invention can also be used in combination with aldose reductase inhibitors. Aldose reductase inhibitors constitute a class of compounds that have become widely known for their utility in preventing and treating conditions arising from complications of diabetes, such as diabetic neuropathy and nephropathy. Such compounds are well known to those skilled in the art and are readily identified by standard biological tests. For example, the aldose reductase inhibitors zopolrestat, 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-, and related compounds are described in U.S. Pat. No. 4,939,140 to Larson et al.
Aldose reductase inhibitors have been taught for use in lowering lipid levels in mammals. See, for example, U. S. Pat. No. 4,492,706 to Kallai-sanfacon and EP 0 310 931 A2 (Ethyl Corporation).
U. S. Pat. No. 5,064,830 to Going discloses the use of certain oxophthalazinyl acetic acid aldose reductase inhibitors, including zopolrestat, for lowering of blood uric acid levels.
Commonly assigned U.S. Pat. No. 5,391,551 discloses the use of certain aldose reductase inhibitors, including zopolrestat, for lowering blood lipid levels in humans. The disclosure teaches that therapeutic utilities derive from the treatment of diseases caused by an increased level of triglycerides in the blood, such diseases include cardiovascular disorders such as thrombosis, arteriosclerosis, myocardial infarction, and angina pectoris. A preferred aldose reductase inhibitor is 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-, also known as zopolrestat.
The term aldose reductase inhibitor refers to compounds that inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase.
Any aldose reductase inhibitor may be used in a combination with a compound of the present invention. Aldose reductase inhibition is readily determined by those skilled in the art according to standard assays (J. Malone, Diabetes, 29:861-864 (1980). xe2x80x9cRed Cell Sorbitol, an indicator of Diabetic Controlxe2x80x9d). A variety of aldose reductase inhibitors are described herein; however, other aldose reductase inhibitors useful in the compositions and methods of this invention will be known to those skilled in the art.
The activity of an aldose reductase inhibitor in a tissue can be determined by testing the amount of aldose reductase inhibitor that is required to lower tissue sorbitol (i.e., by inhibiting the further production of sorbitol consequent to blocking aldose reductase) or lower tissue fructose (by inhibiting the production of sorbitol consequent to blocking aldose reductase and consequently the production of fructose.
Accordingly, examples of aldose reductase inhibitors useful in the compositions, combinations and methods of the present invention include:
1. 3-(4-bromo-2-fluorobenzyl-3,4-dihydro-4-oxo-1-phthalazineacetic acid (ponalrestat, U.S. Pat. No. 4,251,528);
2. N[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (tolrestat, U.S. Pat. No. 4,600,724);
3. 5-[(Z,E)-xcex2-methylinnamytidene]-4-oxo-2-thioxo-3-thiazolideneacetic acid (epalrestat, U.S. Pat. No. 4,464,382, U.S. Pat. No. 4,791,126, U.S. Pat. No. 4,831,045);
4. 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid (zenarestat, U.S. Pat. Nos. 4,734,419, and 4,883,800);
5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic add (U.S. Pat. No. 4,883,410);
6. 2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman4-acetic add (U.S. Pat. No. 4,883,410);
7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid (U.S. Pat. No. 4,771,050);
8. 3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2H-1,4-benzothiazine-2-acetic acid (SPR-210, U.S. Pat. No. 5,252,572);
9. N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methyl-benzeneacetamide (ZD5522, U.S. Pat. No. 5,270,342 and U.S. Pat. No. 5,430,060);
10. (S)-6-fluorospiro[chroman-4xe2x80x2,4xe2x80x2-imidazolidine]-2xe2x80x2,5xe2x80x2-dione (sorbinil, U.S. Pat. No. 4,130,714);
11. d-2-methyl-6-fluoro-spiro(chroman-4xe2x80x2,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No. 4,540,704);
12. 2-fluoro-spiro(9H-fluorene-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No. 4,438,272);
13. 2,7-di-fluoro-spiro(9H-fluorene-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No.4,436,745, U.S. Pat. No. 4,438,272);
14. 2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4xe2x80x2-imidazolidine)-2xe2x80x2,5xe2x80x2-dione (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
15. 7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3xe2x80x2-pyrrolidine)-2,5xe2x80x2-dione (U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);
16. d-cis-6xe2x80x2-chloro-2xe2x80x2,3xe2x80x2-dihydro-2xe2x80x2-methyl-spiro-(imidazolidine4,4xe2x80x2-4xe2x80x2-H-pyrano(2,3-b)pyridine)-2,5-dione (U.S. Pat. No. 4,980,357);
17. spiro[imidazolidine4,5xe2x80x2(6H)-quinoline]2,5-dione-3xe2x80x2-chloro-7, xe2x80x28xe2x80x2-dihydro-7xe2x80x2-methyl-(5xe2x80x2-cis)(U.S. Pat. No. 5,066,659);
18. (2S,4S)-6-fluoro-2xe2x80x2,5xe2x80x2-dioxospiro(chroman-4,4xe2x80x2-imidazolidine)-2-carboxamide (U.S. Pat. No. 5,447,946); and
19. 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3xe2x80x2-pyrrolidine]-1,2xe2x80x2,3,5xe2x80x2(2H)-tetrone (ARI-509, U.S. Pat. No. 5,037,831).
Other aldose reductase inhibitors include compounds having formula Ia below 
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Z is O or S;
R1 is hydroxy or a group capable of being removed in vivo to produce a compound of formula I wherein R1 is OH; and
X and Y are the same or different and are selected from hydrogen, trifluoromethyl, fluoro, and chloro.
A preferred subgroup within the above group of aldose reductase inhibitors includes numbered compounds 1, 2, 3, 4, 5, 6, 9,10, and 17, and the following compounds of Formula Ia:
20. 3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)-4-oxophthalazin-1-yl-acetic acid [R1=hydroxy; X=F; Y=H];
21. 3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Y=F];
22. 3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Cl; Y=H];
23. 3-(5,7-dichlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Y=Cl];
24. 3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-ylacetic acid [R1=hydroxy; X=CF3; Y=H];
25. 3,4dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)-4-oxophthalazin-1-yl-acetic acid [R1=hydroxy; X=F; Y=H];
26. 3-(5,7-diuorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Y=F];
27. 3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Cl; Y=H];
28. 3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1=hydroxy; X=Y=Cl]; and
29. zopolrestat; 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]- [R1=hydroxy; X=trifluoromethyl; Y=H].
In compounds 20-23, and 29 Z is S. In compounds 24-28, Z is O.
Of the above subgroup, compounds 20-29 are more preferred with 29 especially preferred. Procedures for making the aldose reducatase inhibitors of formula Ia can be found in PCT publication number WO 99/26659.
Each of the aldose reductase inhibitors referenced above and other aldose reductase inhibitors can be used in combination with the compounds of the present invention to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.
The compounds of the present invention can also be used in combination with glucocorticoid receptor antagonists. The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells where it resides in the cytosol in an inactive state until it is stimulated by an agonist. Upon stimulation the glucocorticoid receptor translocates to the cell nucleus where it specifically interacts with DNA and/or protein(s) and regulates transcription in a glucocorticoid responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NFxcexa-B. Such interactions result in inhibition of API- and NFxcexa-B-mediated transcription and are believed to be responsible for the anti-inflammatory activity of endogenously administered glucocorticoids. In addition, glucocorticoids may also exert physiologic effects independent of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid receptor agonists exist including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and eliciting GR mediated events, including transcription. RU486 is an example of a non-selectve glucocorticold receptor antagonist. GR antagonists can be used in the treatment of diseases associated with an excess or a deficiency of glucocorticoids in the body. As such, they may be used to treat the following: obesity, diabetes, cardiovascular disease, hypertension, Syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), neurodegeneration (for example, Alzheimer""s and Parkinson""s), cognition enhancement, Cushing""s Syndrome, Addison""s Disease, osteoporosis, frailty, inflammatory diseases (such as osteoarthrits, rheumatoid arthritis, asthma and rhinits), tests of adrenal function, viral infection, immunodeficiency, immunomodulation, autoimmune diseases, allergies, wound healing, compulsive behavior, multi-drug resistance, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical bone fracture, medical catabolism and prevention of muscle frailty. Examples or GR antagonists that can be used in combination with a compound of the present invention include compounds of formula Ib below. 
an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
wherein m is 1 or 2;
- - - represents an optional bond;
A is selected from the group consisting of 
D is CR7, CR7R16, N, NR7 or O;
E is C, CR6 or N;
F is CR4, CR4R5 or O;
G, H and I together with 2 carbon atoms from the A-ring or 2 carbon atoms from the B-ring form a Smembered heterocyclic ring comprising one or more N, O or S atoms; provided that there is at most one of O and S per ring;
J, K, L and M together with 2 carbon atoms from the B-ring forms a 6-membered heterocydic ring comprising 1 or more N atoms;
X is a) absent b) xe2x80x94CH2xe2x80x94, c) xe2x80x94CH(OH)xe2x80x94 or d) xe2x80x94C(O)xe2x80x94;
R1 is a) xe2x80x94H, b) xe2x80x94Zxe2x80x94CH3, c) xe2x80x94(C1-C6)alkyl, d) xe2x80x94(C2-C6)alkenyl, e) xe2x80x94(C2-C6)alkynyl, f) xe2x80x94CHO, g) xe2x80x94CHxe2x95x90Nxe2x80x94OR12, h) xe2x80x94Zxe2x80x94C(O)OR12, i) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, j) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-het, k) xe2x80x94Zxe2x80x94NR12R13, l) xe2x80x94Zxe2x80x94NR12het, m) xe2x80x94Z-het, n) xe2x80x94Zxe2x80x94O-het, o) xe2x80x94Z-arylxe2x80x2, p) xe2x80x94Zxe2x80x94O-arylxe2x80x2, q) xe2x80x94CHOH-arylxe2x80x2 or r) xe2x80x94C(O)-arylxe2x80x2 wherein arylxe2x80x2 in substituents o) to r) is substituted independently with 0, 1 or 2 of the following: xe2x80x94Zxe2x80x94OH, xe2x80x94Zxe2x80x94NR12R13, xe2x80x94Zxe2x80x94NR12-het, xe2x80x94C(O)NR12R13, xe2x80x94C(O)O(C1-C6)alkyl, xe2x80x94C(O)OH, xe2x80x94C(O)-het, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C1-C6)alkyl, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C2-C6)alkenyl, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C2-C6)alkynyl, xe2x80x94NR12xe2x80x94C(O)xe2x80x94Z-het, xe2x80x94CN, xe2x80x94Z-het, xe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94NR12R13, xe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)O(C1-C6)alkyl, xe2x80x94NR12xe2x80x94Zxe2x80x94C(O)O(C1-C6)alkyl, xe2x80x94N(Zxe2x80x94C(O)O(C1-C6)alkyl)2, xe2x80x94NR12xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, xe2x80x94Zxe2x80x94NR12xe2x80x94SO2xe2x80x94R13, xe2x80x94NR12xe2x80x94SO2-het, xe2x80x94C(O)H, xe2x80x94Zxe2x80x94NR12xe2x80x94Zxe2x80x94O(C1-C6)alkyl, xe2x80x94Zxe2x80x94NR12xe2x80x94Zxe2x80x94NR12R13, xe2x80x94Zxe2x80x94NRxe2x80x94(C3-C6)cycloalkyl, xe2x80x94Zxe2x80x94N(Zxe2x80x94O(C1-C6)alkyl)2, xe2x80x94SO2R12, xe2x80x94SOR12, xe2x80x94SR12, xe2x80x94SO2NR12R13, xe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C4)alkyl, xe2x80x94Oxe2x80x94SO2xe2x80x94(C1-C4)alkyl, -halo or xe2x80x94CH3;
Z for each occurrence Is independently a) xe2x80x94(C0-C6)alkyl, b) xe2x80x94(C2-C6)alkenyl or c) xe2x80x94(C2-C6)alkynyl;
R2 is a) xe2x80x94H, b) -halo, c) xe2x80x94OH, d) xe2x80x94(C1-C6)alkyl substituted with 0 or 1 xe2x80x94OH, e) xe2x80x94NR12R13, f) xe2x80x94Zxe2x80x94C(O)O(C1-C6)alkyl, g) xe2x80x94Zxe2x80x94C(O)NR12R13, h) xe2x80x94Oxe2x80x94(C1-C6)alkyl, i) xe2x80x94Zxe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, j) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C3)alkylxe2x80x94C(O)xe2x80x94NR12R13, k) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94O(C1-C6)alkyl, l) xe2x80x94Oxe2x80x94(C2-C6)alkenyl, m) xe2x80x94Oxe2x80x94(C2-C6)alkynyl, n) xe2x80x94Oxe2x80x94Z-het, o) xe2x80x94COOH, p) xe2x80x94C(OH)R12R13 or q) xe2x80x94Zxe2x80x94CN;
R3 is a) xe2x80x94H, b) xe2x80x94(C1-C10)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom is substituted with 0, 1 or 2 Ry, c) xe2x80x94(C2-C10)alkenyl substituted with 0, 1 or 2 Ry, d) xe2x80x94(C2-C10)alkynyl wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0, 1 or 2 Ry, e) xe2x80x94CHxe2x95x90Cxe2x95x90CH2, f) xe2x80x94CN, g) C3-C6)cycloalkyl, h) xe2x80x94Z-aryl, i) xe2x80x94Z-het, j) xe2x80x94C(O)O(C1-C6)alkyl, k) xe2x80x94O(C1-C6)alkyl, l) xe2x80x94Zxe2x80x94Sxe2x80x94R12, m) xe2x80x94Zxe2x80x94S(O)xe2x80x94R12, n) xe2x80x94Zxe2x80x94S(O)2xe2x80x94R12, o) xe2x80x94CH3 p) xe2x80x94NR12Oxe2x80x94(C1-C6)alkyl or q) xe2x80x94CH2ORy;
provided that one of R2 and R3 is absent when there is a double bond between CR2R3 (the 7 position) and the F moiety (the 8 position) of the C-ring;
Ry for each occurrence is independently a) xe2x80x94OH, b) -halo, c) xe2x80x94Zxe2x80x94CH3. d) xe2x80x94Zxe2x80x94CF(C1-C3 alkyl)2, e) xe2x80x94CN, f) xe2x80x94NR12R13, g) xe2x80x94(C3-C6)cycloalkyl, h) xe2x80x94(C3-C6)cycloalkenyl, i) xe2x80x94(C0-C3)alkyl-aryl, j) -het or k) xe2x80x94N3;
or R2 and R3 are taken together to form a) xe2x95x90CHR1 b) xe2x95x90NOR1 c) xe2x95x90O, d) xe2x95x90Nxe2x80x94NR12, e) xe2x95x90Nxe2x80x94NR12xe2x80x94C(O)xe2x80x94R12, f) oxiranyl or g) 1,3-dioxolan-4-yl;
R4 and R5 for each occurrence are independently a) xe2x80x94H, b) xe2x80x94CN, c) xe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, d) xe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C8alkynyl substituted with 0 to 3 halo, f) xe2x80x94Oxe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, g) xe2x80x94Oxe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo, h) xe2x80x94Oxe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo, i) halo, j) xe2x80x94OH, k) (C3-C6)cycloalkyl or l) (C3-C6)cycloalkenyl;
or R4 and R5 are taken together to form xe2x95x90O;
R6 is a) xe2x80x94H, b) xe2x80x94CN, c) xe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, d) xe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo or f) xe2x80x94OH;
R7 and R16 for each occurrence are independently a) xe2x80x94H, b) -halo, c) xe2x80x94CN, d) xe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo or f) xe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo; provided that R7 is other than xe2x80x94CN or -halo when D is NR7;
or R7 and R10 are taken together to form xe2x95x90O;
R6, R9, R14 and R15 for each occurrence are independently a) xe2x80x94H, b) -halo, c) (C1-C6)alkyl substituted with 0 to 3 halo, d) xe2x80x94(C2C6)alkenyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo, f) xe2x80x94CN, g) xe2x80x94(C3-C6)cycloalkyl, h) xe2x80x94(C3-C6)cycloalkenyl, i) xe2x80x94OH, j) xe2x80x94Oxe2x80x94(C1C6)alkyl, k) xe2x80x94Oxe2x80x94(C1-C6)alkenyl, l) xe2x80x94Oxe2x80x94(C1-C6)alkynyl, m) xe2x80x94NR12R13, n) xe2x80x94C(O)OR12 or o) xe2x80x94C(O)NR12R13;
or R8 and R9 are taken together on the C-ring to form xe2x95x90O; provided that when m 1s 2, only one set of R8 and R9 are taken together to form xe2x95x90O;
or R14 and R15 are taken together to form xe2x95x90O; provided that when R14 and R15 are taken together to form xe2x95x90O, D is other than CR7 and E is other than C;
R10 is a) xe2x80x94(C1-C10)alkyl substituted with 0 to 3 substituents independently selected from -halo, xe2x80x94OH and xe2x80x94N3, b) xe2x80x94(C2-C10)alkenyl substituted with 0 to 3 subsuituents independently selected from -halo, xe2x80x94OH and xe2x80x94N3, c) xe2x80x94(C2-C10)alkynyl substituted with 0 to 3 substituents independently selected from -halo, xe2x80x94OH and xe2x80x94N3, d) -halo, e) xe2x80x94Zxe2x80x94CN, f) xe2x80x94OH, g) xe2x80x94Z-het, h) xe2x80x94Zxe2x80x94NR12R13, i) xe2x80x94Zxe2x80x94C(O)-het, j) xe2x80x94Zxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, k) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, l) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12Zxe2x80x94CN, m) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-het, n) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-aryl, o) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Zxe2x80x94NR12R13, p) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Zxe2x80x94O(C1-C6)alkyl, q) xe2x80x94(C1-C6)alkyl-C(O)OH, r) xe2x80x94Zxe2x80x94C(O)O(C1-C6)alkyl, s) xe2x80x94Zxe2x80x94Oxe2x80x94(C0-C6)alkyl-het, t) xe2x80x94Zxe2x80x94Oxe2x80x94(C0-C6)alkyl-aryl, u) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C6)alkyl substituted with 0 to 2 Rx, v) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C6)alkyl-CH(O), w) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C6)alkyl-NR12-het, x) xe2x80x94Zxe2x80x94Oxe2x80x94Z-hetxe2x80x94Z-het, y) xe2x80x94Zxe2x80x94Oxe2x80x94Z-hetxe2x80x94Zxe2x80x94NR12R13, z) xe2x80x94Zxe2x80x94Oxe2x80x94Z-het-C(O)-het, a1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)-het, b1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)-het-het, c1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, d1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(S)xe2x80x94NR12R13, e1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, f1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94NR12R13, g1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94O(C1-C6)alkyl, h1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94OH, i1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94O(C1-C6)alkyl, j1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94OH, k1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Zxe2x80x94NR12R13, l1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-het, m1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94SO2xe2x80x94(C1-C6)alkyl, n1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(xe2x95x90NR12)(NR12R13), o1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(xe2x95x90NOR12)(NR12R13), p1) xe2x80x94Zxe2x80x94NR12xe2x80x94C(O)xe2x80x94Oxe2x80x94Zxe2x80x94NR12R13, q1) xe2x80x94Zxe2x80x94Sxe2x80x94C(O)xe2x80x94NR12R13, r1) xe2x80x94Zxe2x80x94Oxe2x80x94SO2xe2x80x94(C1-C6)alkyl, s1) xe2x80x94Zxe2x80x94Oxe2x80x94SO2-aryl, t1) xe2x80x94Zxe2x80x94Oxe2x80x94SO2xe2x80x94NR12R13, u1l) xe2x80x94Zxe2x80x94Oxe2x80x94SO2xe2x80x94CF3, v1) xe2x80x94Zxe2x80x94NR12C(O)OR13 or w1) xe2x80x94Zxe2x80x94NR12C(O)R13;
or R9 and R10 are taken together on the moiety of formula A-5 to form a) xe2x95x90O or b) xe2x95x90NOR12;
R11 is a) xe2x80x94H, b) xe2x80x94(C1-C5)alkyl, c) xe2x80x94(C3-C6)cycloalkyl or d) xe2x80x94(C0-C3)alkyl-aryl;
R12 and R13 for each occurrence are each independently a) xe2x80x94H, b) xe2x80x94(C1-C6)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom Is substituted with 0 to 6 halo, c) xe2x80x94(C2-C6)alkenyl substituted with 0 to 6 halo or d) xe2x80x94(C1-C6)alkynyl wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0 to 6 halo;
or R12 and R13 are taken together with N to form het;
or R6 and R14 or R15 are taken together to form 1,3-dioxolanyl;
aryl is a) phenyl substituted with 0 to 3 Rx, b) naphthyl substituted with 0 to 3 Rx or c) biphenyl substituted with 0 to 3 Rx;
het is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocydic rings is fused to a benzene ring or another heterocycle; and the nitrogen may be in the oxidized state giving the N-oxide form; and substituted with 0 to 3 Rx;
Rx for each occurrence is independently a) -halo, b) xe2x80x94OH, c) xe2x80x94(C1-C6)alkyl, d) xe2x80x94(C2-C6)alkenyl, e) xe2x80x94(C2-C6)alkynyl, f) xe2x80x94O(C1-C6)alkyl, g) xe2x80x94O(C2-C6)alkenyl, h) xe2x80x94O(C2-C6)alkynyl, i) xe2x80x94(C0-C6)alkyl-NR12R13, j) xe2x80x94C(O)xe2x80x94NR12R13, k) xe2x80x94Zxe2x80x94SO2R12, l) xe2x80x94Zxe2x80x94SOR12, m) xe2x80x94Zxe2x80x94SR12, n) xe2x80x94NR12xe2x80x94SO2R13, o) xe2x80x94NR12xe2x80x94C(O)xe2x80x94R13, p) xe2x80x94NR12xe2x80x94OR13, q) xe2x80x94SO2xe2x80x94NR12R13, r) xe2x80x94CN, s) xe2x80x94CF3, t) xe2x80x94C(O)(C1-C6)alkyl, u) xe2x95x90O, v) xe2x80x94Zxe2x80x94SO2-phenyl or w) xe2x80x94Zxe2x80x94SO2-hetxe2x80x2;
arylxe2x80x2 is phenyl, naphthyl or biphenyl;
hetxe2x80x2 is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicydic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle;
provided that:
1) Xxe2x80x94R1 is other than hydrogen or methyl;
2) when R9 and R10 are substituents on the A-ring, they are other than mono- or di-methoxy;
3) when R2 and R3 are taken together to form xe2x95x90CHR11 or xe2x95x90O wherein R11 is xe2x80x94O(C1-C6)alkyl, then xe2x80x94Xxe2x80x94R1 is other than (C1-C4)alkyl;
4) when R2 and R3 taken together are Cxe2x95x90O and R9 is hydrogen on the A-ring; or when R2 is hydroxy, R3 is hydrogen and R9 is hydrogen on the A-ring, then R10 is other than xe2x80x94Oxe2x80x94(C1-C6)alkyl or xe2x80x94Oxe2x80x94CH2-phenyl at the 2-position of the A-ring;
5) when Xxe2x80x94R1 is (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl, R9 and R10 are other than mono-hydroxy or xe2x95x90O, including the diol form thereof, when taken together; and
6) when X is absent, R1 is other than a moiety containing a heteroatom independently selected from N, O or S directly attached to the juncture of the B-ring and the C-ring. (See U.S. Provisional Patent Application No. 60/132,130)
Each of the glucocorticoid receptor antagonists referenced above and other glucocorticoid receptor antagonists can be used in combination with the compounds of the present invention to treat or prevent diabetes, hyperglycemia, hyperdholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.
The compounds of the present invention can also be used in combination with sorbitol dehydrogenase inhibitors. Sorbitol dehydrogenase inhibitors lower fructose levels and have been used to treat or prevent diabetic complications such as neuropathy, retinopathy, nephropathy, cardiomyopathy, microangiopathy, and macroangiopathy. U.S. Pat. Nos. 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitof dehydrogenase.
Each of the sorbitol dehydrogenase inhibitors referenced above and other sorbitol dehydrogenase inhibitors can be used in combination with the compounds of the present invention to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.
The compounds of the present invention can also be used in combination with sodium-hydrogen exchanger type 1 (NHE-1) inhibitors. NHE-1 inhibitors can be used to reduce tissue damage resulting from ischemia. Of great concern is tissue damage that occurs as a result of ischemia in cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, or intestinal tissue. NHE-1 inhibitors can also be administered to prevent perioperative myocardial ischemic injury.
Examples of NHE-1 inhibitors include a compound having the Formula Ic 
Formula Ic
a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug, wherein
Z is carbon connected and is a five-membered, diaza, diunsaturated ring having two contiguous nitrogens, said ring optionaily mono-, di-, or tri-substituted with up to three substituents independently selected from R1 R2 and R3; or
Z is carbon connected and is a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R4 and R5;
wherein R1, R2, R3, R4 and R5 are each independently hydrogen, hydroxy(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkylthio, (C3-C4)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C1-C4)alkoxy, ( C1-C4)alkoxy(C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkyfcarbamoyl, M or M(C1-C4)alkyl, any of said previous (C1-C4)alkyl moieties optionally having from one to nine fluorines; said (C1-C4)alkyl or (C3-C4)cycloalkyl optionally mono-or di-substituted independently with hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl; and said (%C4)cycloalkyl optionally having from one to seven fluorines;
wherein M is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms cn selected independently from oxygen, sulfur and nitrogen, or, a bicydic ring C, consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said M is optionally substituted, on one ring if the moiety is monocydic, or one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C1-C4)alkyl and additionally R6, R7 and R8 are optionally hydroxy, nitro, halo, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl, formyl, (C1-C4)alkanoyl, (C1-C4)alkanoyloxy, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl, (C1-C4)alkenyl, (C1-C4)alkynyl or (C5-C7)cydoalkenyl,
wherein said (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C7)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkylamino or (C3-7)Cycloalkyl R6, R7 and R8 substituents are optionally mono- substituted independently with hydroxy, (C1-C4)alkoxycarbonyl, (C3-C7)cycloalkyl, (C1-C4)alkanoyl, (C1-C4)alkanoylamino, (C1-C4)alkanoyloxy, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkyfsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, hiol, nitro, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono- N- or di-N,N-(C1-C4)alkylaminosulfonyl or optionally substituted with one to nine fluorines. (See PCT patent appiciation number PCT/IB99/00206).
Each of the NHE-1 inhibitors referenced above and other NHE-1 inhibitors can be used in combination with the compounds of the present invention to treat or prevent diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.